US9198988B2 - Nanoparticulate manganese MRI contrast agents - Google Patents
Nanoparticulate manganese MRI contrast agents Download PDFInfo
- Publication number
- US9198988B2 US9198988B2 US13/979,685 US201113979685A US9198988B2 US 9198988 B2 US9198988 B2 US 9198988B2 US 201113979685 A US201113979685 A US 201113979685A US 9198988 B2 US9198988 B2 US 9198988B2
- Authority
- US
- United States
- Prior art keywords
- nanoparticles
- contrast agent
- manganese
- agent composition
- ions
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
Links
- 239000002616 MRI contrast agent Substances 0.000 title claims abstract description 22
- 239000011572 manganese Substances 0.000 title claims description 36
- 229910052748 manganese Inorganic materials 0.000 title claims description 16
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 title claims description 13
- -1 manganese(II) ions Chemical class 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000013078 crystal Substances 0.000 claims abstract description 6
- 239000002872 contrast media Substances 0.000 claims description 48
- 239000002105 nanoparticle Substances 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 claims description 24
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229910002553 FeIII Inorganic materials 0.000 claims description 10
- 238000000338 in vitro Methods 0.000 claims description 10
- 229910052744 lithium Inorganic materials 0.000 claims description 10
- 229910052700 potassium Inorganic materials 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 9
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 8
- 241000282414 Homo sapiens Species 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 229910003202 NH4 Inorganic materials 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 239000011248 coating agent Substances 0.000 claims description 7
- 238000000576 coating method Methods 0.000 claims description 7
- 239000003456 ion exchange resin Substances 0.000 claims description 7
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 7
- 229920000249 biocompatible polymer Polymers 0.000 claims description 6
- 229910052742 iron Inorganic materials 0.000 claims description 6
- 229910002547 FeII Inorganic materials 0.000 claims description 5
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 5
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- 230000005291 magnetic effect Effects 0.000 claims description 5
- 239000011565 manganese chloride Substances 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 229910052804 chromium Inorganic materials 0.000 claims description 3
- 230000005298 paramagnetic effect Effects 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- MWVTWFVJZLCBMC-UHFFFAOYSA-N 4,4'-bipyridine Chemical compound C1=NC=CC(C=2C=CN=CC=2)=C1 MWVTWFVJZLCBMC-UHFFFAOYSA-N 0.000 claims description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000010253 intravenous injection Methods 0.000 claims description 2
- 235000002867 manganese chloride Nutrition 0.000 claims description 2
- 229940099607 manganese chloride Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 2
- 150000001340 alkali metals Chemical class 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- 239000011591 potassium Substances 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 230000003993 interaction Effects 0.000 claims 1
- 230000017531 blood circulation Effects 0.000 abstract description 6
- 229910052751 metal Inorganic materials 0.000 abstract description 5
- 239000002184 metal Substances 0.000 abstract description 5
- 150000002825 nitriles Chemical class 0.000 abstract description 3
- 230000035945 sensitivity Effects 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 150000002433 hydrophilic molecules Chemical class 0.000 abstract 1
- 239000011234 nano-particulate material Substances 0.000 abstract 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 18
- 238000002595 magnetic resonance imaging Methods 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229910001447 ferric ion Inorganic materials 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- QDQFSBKXQQZVTB-UHFFFAOYSA-F 2-[2-[carboxylatomethyl-[[2-methyl-3-oxido-5-(phosphonatooxymethyl)pyridin-4-yl]methyl]amino]ethyl-[[2-methyl-3-oxido-5-(phosphonatooxymethyl)pyridin-4-yl]methyl]amino]acetate;manganese(2+) Chemical compound [Mn+2].CC1=NC=C(COP([O-])([O-])=O)C(CN(CCN(CC([O-])=O)CC=2C(=C(C)N=CC=2COP([O-])([O-])=O)[O-])CC([O-])=O)=C1[O-] QDQFSBKXQQZVTB-UHFFFAOYSA-F 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- 208000003510 Nephrogenic Fibrosing Dermopathy Diseases 0.000 description 3
- 206010067467 Nephrogenic systemic fibrosis Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000003642 reactive oxygen metabolite Substances 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 229910052688 Gadolinium Inorganic materials 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000007541 cellular toxicity Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- UETZVSHORCDDTH-UHFFFAOYSA-N iron(2+);hexacyanide Chemical compound [Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] UETZVSHORCDDTH-UHFFFAOYSA-N 0.000 description 2
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910001425 magnesium ion Inorganic materials 0.000 description 2
- 229940031182 nanoparticles iron oxide Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000006478 transmetalation reaction Methods 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- DPNNNPAKRZOSMO-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-10-(2-hydroxypropyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid;gadolinium(3+) Chemical compound [Gd+3].CC(O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 DPNNNPAKRZOSMO-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229930091051 Arenine Natural products 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000008857 Ferritin Human genes 0.000 description 1
- 238000008416 Ferritin Methods 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 108010033576 Transferrin Receptors Proteins 0.000 description 1
- 102000007238 Transferrin Receptors Human genes 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013257 coordination network Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 108010046015 ferritin receptor Proteins 0.000 description 1
- 229910001448 ferrous ion Inorganic materials 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- OCDAWJYGVOLXGZ-VPVMAENOSA-K gadobenate dimeglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)C(C([O-])=O)COCC1=CC=CC=C1 OCDAWJYGVOLXGZ-VPVMAENOSA-K 0.000 description 1
- ZPDFIIGFYAHNSK-UHFFFAOYSA-K gadobutrol Chemical compound [Gd+3].OCC(O)C(CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-UHFFFAOYSA-K 0.000 description 1
- HZHFFEYYPYZMNU-UHFFFAOYSA-K gadodiamide Chemical compound [Gd+3].CNC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC(=O)NC HZHFFEYYPYZMNU-UHFFFAOYSA-K 0.000 description 1
- PIZALBORPSCYJU-QSQMUHTISA-H gadofosveset Chemical compound O.[Na+].[Na+].[Na+].[Gd+3].C1CC(OP([O-])(=O)OC[C@@H](CN(CCN(CC([O-])=O)CC([O-])=O)CC(=O)[O-])N(CC([O-])=O)CC([O-])=O)CCC1(C=1C=CC=CC=1)C1=CC=CC=C1 PIZALBORPSCYJU-QSQMUHTISA-H 0.000 description 1
- LGMLJQFQKXPRGA-VPVMAENOSA-K gadopentetate dimeglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O LGMLJQFQKXPRGA-VPVMAENOSA-K 0.000 description 1
- RYHQMKVRYNEBNJ-BMWGJIJESA-K gadoterate meglumine Chemical compound [Gd+3].CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 RYHQMKVRYNEBNJ-BMWGJIJESA-K 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000005283 ground state Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000002075 inversion recovery Methods 0.000 description 1
- 150000002506 iron compounds Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000005415 magnetization Effects 0.000 description 1
- 229910001437 manganese ion Inorganic materials 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- DRKHJSDSSUXYTE-UHFFFAOYSA-L oxidanium;2-[bis[2-[carboxylatomethyl-[2-(2-methoxyethylamino)-2-oxoethyl]amino]ethyl]amino]acetate;gadolinium(3+) Chemical compound [OH3+].[Gd+3].COCCNC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC(=O)NCCOC DRKHJSDSSUXYTE-UHFFFAOYSA-L 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 231100000857 poor renal function Toxicity 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000000264 spin echo pulse sequence Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229910001428 transition metal ion Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229910006297 γ-Fe2O3 Inorganic materials 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/32—Manganese; Compounds thereof
Definitions
- Nanoparticles of various metal cyanide compounds containing manganese(II) ions in the crystal lattice having very low release of free Mn 2+ ions, very low cyanide toxicity and high relaxivity values are suitable as MRI contrast agents.
- the nanoparticles are surface modified with a water-soluble and biocompatible polymer, have long blood circulation half lives, and can be used at low concentrations with low- and high-magnetic field scanners to enhance magnetic resonance imaging (MRI) contrast.
- MRI magnetic resonance imaging
- MRI magnetic resonance imaging
- the MRI signal intensity (SI) from different body tissues varies with the content of water protons present in the tissue and with both the longitudinal (T 1 ) and transverse (T 2 ) relaxation times of those protons. In some cases, the variation of water content in different tissues is sufficient to produce image contrast. In other cases, it is necessary to use a contrast agent to enhance the image contrast.
- Chemical compounds that can change the relaxation times, either T 1 or T 2 , within a tissue are routinely used as contrast agents in MRI in the medical diagnosis of diseases and/or organ functions in the human body.
- Clinical MRI contrast agents can be divided into two classes, T 1 agents and T 2 agents.
- a T 1 or positive contrast agent shortens the longitudinal relaxation time (T 1 ) of water protons, and can brighten regions where the agent is present.
- a T 2 or negative contrast agent reduces the transverse relaxation time (T 2 ) of water protons, and produces darkened spots in the tissues reached by the agent when a residual transverse magnetization is used in a spin-echo experiment.
- T 1 contrast agents have been developed from the use of the paramagnetic Gd 3+ ion chelated by various low molecular weight polyaminopolycarboxylate ligands.
- the high electronic spin (4f 7 , S 7/2, 7.9 BM), coupled with a symmetric electronic ground state ( 8 S 7/2 ) and slow electronic relaxation (10 ⁇ 9 s), gives Gd(III) unique nuclear-magnetic properties for enhancing T 1 -relaxation of protons from bulk water.
- Currently, there are nine commercial T 1 agents approved worldwide for clinical use ( FIG. 1 and Table 1).
- the major drawback of these agents is their limited sensitivity (relaxivity).
- the relaxivity of a contrast agent is the measure of its efficacy and usually expressed as the concentration-normalized amount of increase in the longitudinal relaxation rate 1/T 1 per millimole of agent in the unit of mM ⁇ 1 ⁇ s ⁇ 1 .
- MR imaging applications using such agents require high tissue concentrations (0.1-0.6 mM).
- Relaxivity of these agents drops significantly at higher magnetic fields, which makes them inefficient in the high-field MR scanners for clinical diagnostic imaging.
- the high-field scanners can greatly shorten data acquisition time, improve signal-to-noise ratio (SNR) and provide higher spatial resolution.
- SNR signal-to-noise ratio
- NSF nephrogenic systemic fibrosis
- the toxicity of gadolinium stems from the fact that the ionic radius of Gd(III) (1.02 ⁇ ) is very similar to that of calcium(II) (1.00 ⁇ ).
- the presence of this heavy metal ion in the body can disrupt the normal functions of many types of voltage-gated Ca 2+ -channels at the nano- to micro-molar concentration level.
- these small molecule-based T 1 contrast agents function only as extracellular agents, which limits their use in detecting biological receptors or markers within the cell and makes them ineffective as cellular MR probes.
- T 2 contrast agents are based on superparamagnetic iron oxide nanoparticles (SPIOs). These agents shorten the transverse relaxation time (T 2 ) of bulk water to produce a negative or darkened contrast.
- SPIOs superparamagnetic iron oxide nanoparticles
- T 2 transverse relaxation time
- SPIOs are nontoxic and FDA-approved contrast agents with higher sensitivity and can penetrate cells, from the standpoint of clinical diagnosis and cellular imaging, the image contrast produced by such agents is far less desirable than that by the T 1 agents. It is difficult to distinguish between the darkened spots produced by the accumulation of a T 2 agent and the signals caused by bleeding, calcification, metal deposit, or other artifacts from the background. This fact can complicate the correct interpretation of imaging results, and is a major barrier for T 2 agents to gain widespread clinical applications in replacement of T 1 agents. Besides this, imaging with T 2 contrast requires longer acquisition times.
- the primary application of SPIOs T 2 agents is for image-guided drug delivery and the monitoring of surgical procedures.
- any Fe 3+ -containing compound administered parenterally can disturb the iron homeostasis that is tightly regulated by ferritin and transferrin receptors in the body.
- the ferrous ion Fe 2+ produced from any non-sequestered ferric ion through reduction by a variety of biomolecules, can catalyze the generation of reactive oxygen species (ROS) including hydroxyl radical and peroxide radical via the so-called Fenton chemistry: Fe 2+ +H 2 O 2 ⁇ Fe 3+ +OH.+OH ⁇ (1) Fe 3+ +H 2 O 2 ⁇ Fe 2+ +OOH.+H + (2)
- Mn 2+ -based small-molecule complex has been developed as a MRI contrast agent, namely manganese dipyridoxal diphosphate (MnDPDP) for application to liver, pancreas, and heart.
- MnDPDP manganese dipyridoxal diphosphate
- the Mn 2+ is shown to be released in vivo due to the transmetallation with zinc(II). Therefore, the contrast enhancement detected in these organs is due to the presence of the released paramagnetic Mn 2+ ions.
- the cellular toxicity of higher level manganese (>1 mM) has prevented any Mn 2+ -complex from being developed as the generalized MRI contrast agent. It is well known that exposure to high concentration level of Mn 2+ can lead to neurological deficits, particularly a neurological disorder resembling Parkinson's disease.
- This invention describes a synthetic procedure for preparing nanoparticles from a class of metal cyanide compounds whose surfaces are coated with a water-soluble and biocompatible polymer.
- Such nanoparticles have long blood circulation half lives, very low release of free Mn +2 ions, very low cyanide toxicity, high relaxivity values and can be used at low and high magnetic fields as non-gadolinium containing MRI contrast agents.
- a process for preparing a manganese(II) contrast agent composition comprising the steps of: treating a hexacyanometallate with a H-form ion exchange resin and then mixing with manganese chloride and an organic amine or an alkali metal hydroxide or carbonate and forming a manganese(II) contrast agent.
- FIG. 1 relates to schematic structures of common MR contrast agents with one coordinated water molecule omitted from each structure for clarity;
- FIG. 2 is the crystal structure of KMn[Fe III (CN)6]
- FIG. 3 is a diagram showing the Mn 2+ ion leaching results under different pH conditions
- FIG. 4 shows the proton T 1 (top) and T 2 (bottom) relaxation rate versus concentration of Mn 2+ ion at 11.7 T;
- FIG. 5 shows the proton T 1 (top) and T 2 (bottom) relaxation rate versus concentration of Mn 2+ ion at 7.0 T.
- both metal ions and CN ⁇ ligand are completely locked in the lattice positions and generally cannot be released from the compound.
- a result is that very low amounts of Mn 2+ ions are released and thus the compounds there are considered stable and have very low toxicity.
- Blood circulation half lives of the contrast agents of the present invention generally range from about 0.1 to 2 hours, desirably from about 0.25 to about 2.0 hours and preferably from about 0.5 to about 2.0 hours.
- the concentrations of the manganese contrast agents in water that can be utilized for application to an animal such as a human being for an MRI analysis are amounts generally from about 1 micromole to about 150 millimoles, desirably from about 10 micromolar to about 100 millimolar and preferably from about 25 micromolar to about 50 millimolar per liter of solution.
- the manganese(II) hexacyanometallate nanoparticles are made using conventional methods known to the art and to the literature, having diameters generally from about 4 to about 500 nm, desirably from about 6 to about 200 nm and preferably from about 8 to about 100 nm.
- the particle diameter size is important in that it results in long circulation times in the blood stream before it is removed by the body. In contrast thereto, very small diameter sizes such as less than 2 nm or less than 1 nm are avoided since they are readily removed from the human body and have a short residence time therein, for example less than 20 minutes that is unacceptable for use as a MRI contrast agent.
- the manganese contrast agents of the present invention are adapted to be applied to the body as dispersed nanoparticles in a solvent such as water stabilized by a hydrophilic coating comprising a carboxylic acid or a hydrophilic biocompatible polymer, or both.
- a hydrophilic coating comprising a carboxylic acid or a hydrophilic biocompatible polymer, or both.
- the hydrophilic coating acts to make the otherwise insoluble manganese(II) nanoparticles dispersible in water, and thus promoting water stability of such nanoparticles while providing a protection shell against nanoparticle aggregation and precipitation.
- Suitable carboxylic acids include, but are not limited to, common carboxylic acids such as acetic acid, oxalic acid, citric acid, tartaric acid, adipic acid, gluconic acid, and other mono-, di-, tri- or polycarboxylic acids.
- Suitable hydrophilic biocompatible polymer used for coating to prolong blood circulation times, reduced biological toxicity, and particle solution stability against aggregation and precipitation include, but are not limited to, polyethylene glycol (PEG), chitosan, dextran, e.g., polymers of glucose having number average molecular weights up to 200,000, and polyvinylpyrrolidone (PVP).
- the manganese contrast agent aqueous solutions are generally stable in acidic to neutral solutions with a pH value from about 1 to about 7.5, desirably from about 2.5 to about 7.5, and preferably from about 3.5 to about 7.3.
- a general procedure for preparation of nanoparticulate Mn 2 [Fe(CN) 6 ] MRI contrast agents comprises the following reactions: K 4 [Fe(CN) 6 ]+H-form ion exchange resin ⁇ H 4 [Fe(CN) 6 ] 2MnCl 2 +H 4 [Fe(CN) 6 ]+triethylamine ⁇ Mn 2 [Fe(CN) 6 ]
- H-form ion exchange resin can be used with suitable examples including AMBERLITETM IR120 H from Dow Chemical Company, a styrene divinylbenzene copolymer with sulfonic acid groups, AG 50W-X2 from Bio-Rad, a cation exchange resin, and AMBERLYSTTM 16 West from Rohm and Hass, a sulfonic acid ion exchange resin.
- the suitable organic amine compounds include, but not limited to, amines having from 3 to about 12, and desirably from 3 to about 10 carbon atoms such as triethylamine, benzylamine, ethylenediamine, piperidine, pyridine, pyrazine, 2,2′-bipyridine and 4,4′-bipyridine, or any combination thereof.
- the manganese(II) contrast agents of the present invention can be prepared as follows:
- a proper concentration, i.e. 10 ⁇ 3 to 10 3 M, of K 4 [Fe(CN) 6 ] was first treated with a proper amount of H-form ion exchange resin, i.e. about 1 gram to about 1,000 grams and desirably from about 5 to about 500 grams, to yield H 4 [Fe(CN) 6 ] that was then mixed with a proper concentration, i.e. 10 ⁇ 3 to 10 3 M and desirably from about 0.01 to about 1.00 M of MnCl 2 in the presence of a proper amount of triethylamine, i.e. 0.01 gram to 10 grams and desirably from about 0.05 to about 5.00 grams, citric acid, i.e.
- reaction temperatures of the first reaction range from about 0 to about 100° C. and desirably from about 5 to about 95° C.
- the reaction temperature with respect to the second reaction generally range from about 0 to about 100° C. and desirably from about 5 to about 95° C.
- the reaction conditions are generally limited by the freezing point and boiling point of water.
- Mn 2 [Fe(CN) 6 ] When other manganese contrast agents other than Mn 2 [Fe(CN) 6 ] are desired, the process is essentially similar except that the ratios of the above noted compounds are changed. For example, if Mn 3 [Fe III (CN) 6 ] 2 is desired, a proper concentration, i.e. 10 ⁇ 3 to 10 3 M of K 3 [Fe(CN) 6 ] can be treated with a proper amount of H-form ion exchange resin and allowed to react with a proper concentration, i.e.
- nanoparticles of the formula Mn 2 [Fe(CN) 6 ] were treated with 20 parts of a saline solution, e.g. a NaCl solution having a pH of 1, 3, 5, and 7 and incubated at room temperatures for 16 hours.
- a saline solution e.g. a NaCl solution having a pH of 1, 3, 5, and 7
- the potential transmetallation reactions between the nanoparticles and solutions each containing the following ions: 1 mM Ca 2+ , 1 mM Mg 2+ , 1 mM K + or 1 mM Zn 2+ ions were also studied.
- the results were analyzed by Atomic Adsorption (AA) and showed that the highest Mn concentration found has ⁇ 19 ppm, which is much less than the minimal toxic level of 0.1 mM, see FIG. 3 .
- the Mn 2+ release amounts were higher at lower pH levels and essentially nil when utilized with magnesium and calcium ions.
- the release rate of the Maganese(II) hexacyanoferrate with respect to Mn 2+ is approximately 2,000 times less than the release rate of MnDPDP.
- release rates of at least about 25, about 50, about 100, about 500, or about 1,000 times less than the release rate of MnDPDP can be readily obtained.
- the in vitro release rate of Mn 2+ at a pH of about 7 is from about 10 to about 20, desirably from about 12 to 18, and preferably from about 14 to about 16 parts per million in water for a 24 hour time period.
- FIG. 3 also shows that the release rate of manganese in the presence of other ions at a pH of 7 such as zinc, magnesium, and calcium was also extremely low.
- the concentrations of free cyanide ions released from manganese(II) hexacyanoferrate MRI contrast agents of the present invention is generally at the level of ⁇ 10 ppm, which is about 10 to 15 times less than a minimum toxic level of 0.1 mM currently set forth by the EPA. That is, the in vitro concentration of free cyanide ions released by the MRI contrast agents of the present invention is generally about 2 to about 50, and desirably from about 5 to about 30 times less than the current minimum toxic EPA level of 0.1 mM of free CN ⁇ ions. These values are determined based upon the release rate of free cyanide ions in water during a 24 hour time period at room temperature, e.g. about 65 to about 85° F.
- the manganese contrast agents of the present invention thus essentially have no toxicity and are very safe for use in MRI scanning.
- the in vitro T 1 (positive contrast values) of the MRI contrast agents of the present invention have relaxivity values, i.e. r 1 , of from about 1 to about 15, desirably from about 2 to about 15, and preferably from about 4 or about 6 to about 14 mM ⁇ 1 ⁇ s ⁇ 1 /mM of Mn +2 ions.
- the T 2 (negative contrast agents) of in vitro relaxivity values, i.e. r 2 is from about 50 to about 300, desirably from about 170 to about 250, and preferably from about 100 to about 200 mM ⁇ 1 ⁇ s ⁇ 1 /mM of Mn +2 ions.
- manganese MRI contrast agents can be utilized in either high or low magnetic field strength such as from about 0.5 to about 11 Tesla and desirably from about 1.0 to about 9.0 Teslas.
- the manganese contrast agents of the present invention can be utilized where ever MRI contrast agents have been utilized heretofore and the same is well known to the art and to the literature including the administration thereof.
- the contrast agent can be utilized with respect to various animals including pets such as dogs, cats, horses, cattle, pigs, goats, chickens, turkeys, etc.
- a highly preferred end use is for MRI diagnosis of human beings, i.e. persons, as by various well known methods such as oral administration, intravenous injection, and the like.
Landscapes
- Health & Medical Sciences (AREA)
- Nanotechnology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Radiology & Medical Imaging (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
TABLE 1 |
Stability constants and relaxivity values |
for the commercial MRI contrast agents |
Trademark | LogKGdL | r1(mM−1 × s−1) | ||
Dotarem ® | 25.3 | 4.2 | ||
ProHance ® | 23.8 | 4.4 | ||
Gadovist ® | 20.8 | 5.3 | ||
Magnevist ® | 22.2 | 4.3 | ||
Omniscan ® | 16.8 | 4.6 | ||
OptiMARK | 16.8 | 5.2 | ||
MultiHance | 18.4 | 6.7 | ||
Primovist | 23.5 | 7.3 | ||
Vasovist | 23.2 | 19 | ||
Fe2++H2O2→Fe3++OH.+OH− (1)
Fe3++H2O2→Fe2++OOH.+H+ (2)
K4[Fe(CN)6]+H-form ion exchange resin→H4[Fe(CN)6]
2MnCl2+H4[Fe(CN)6]+triethylamine→Mn2[Fe(CN)6]
Claims (18)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/979,685 US9198988B2 (en) | 2011-02-08 | 2011-08-29 | Nanoparticulate manganese MRI contrast agents |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161462804P | 2011-02-08 | 2011-02-08 | |
PCT/US2011/001520 WO2012108856A1 (en) | 2011-02-08 | 2011-08-29 | Nanoparticulate manganese mri contrast agents |
US13/979,685 US9198988B2 (en) | 2011-02-08 | 2011-08-29 | Nanoparticulate manganese MRI contrast agents |
Publications (2)
Publication Number | Publication Date |
---|---|
US20130302256A1 US20130302256A1 (en) | 2013-11-14 |
US9198988B2 true US9198988B2 (en) | 2015-12-01 |
Family
ID=46638855
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/979,685 Expired - Fee Related US9198988B2 (en) | 2011-02-08 | 2011-08-29 | Nanoparticulate manganese MRI contrast agents |
Country Status (2)
Country | Link |
---|---|
US (1) | US9198988B2 (en) |
WO (1) | WO2012108856A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3354375A1 (en) | 2017-01-27 | 2018-08-01 | Universite Paris Nord | Nanomaterial and method of production of a nanomaterial for medical applications, such as mri or sers |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9561183B2 (en) | 2013-03-15 | 2017-02-07 | Children's National Medical Center | Prussian blue-inspired constructs for multimodal imaging and therapy |
CN106581057B (en) * | 2016-11-02 | 2020-06-12 | 中国科学院上海硅酸盐研究所 | Nanometer diagnosis and treatment agent based on prussian blue analogue and preparation method and application thereof |
EP3774826A4 (en) * | 2018-04-13 | 2022-04-13 | Rux Energy Pty Ltd | Multifunctional co-ordination framework materials |
CN114804152A (en) * | 2021-06-09 | 2022-07-29 | 吴学文 | KMn 3+ [Fe 2+ (CN) 6 ]Preparation method of (1) |
CN113456836B (en) * | 2021-07-07 | 2022-09-16 | 中国科学院精密测量科学与技术创新研究院 | Manganese-heme coordination polymer nanoparticle and preparation method and application thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100133487A1 (en) | 2006-12-28 | 2010-06-03 | National Institute Of Advanced Industrial Science And Technology | Method of producing prussian blue-type metal complex nanoparticles, and prussian blue-type metal complex nanoparticles obtained by the method, dispersion of the nanoparticles, method of regulating the color of the nanoparticles, and electrode and transmitted light-regulator each using the nanoparticles |
US20100215587A1 (en) | 2009-02-23 | 2010-08-26 | Kent State University | Materials and methods for mri contrast agents and drug delivery |
US20100254912A1 (en) | 2009-04-03 | 2010-10-07 | Kent State University | Gadolinium containing prussian blue nanoparticles as nontoxic MRI contrast agents having high relaxivity |
-
2011
- 2011-08-29 WO PCT/US2011/001520 patent/WO2012108856A1/en active Application Filing
- 2011-08-29 US US13/979,685 patent/US9198988B2/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100133487A1 (en) | 2006-12-28 | 2010-06-03 | National Institute Of Advanced Industrial Science And Technology | Method of producing prussian blue-type metal complex nanoparticles, and prussian blue-type metal complex nanoparticles obtained by the method, dispersion of the nanoparticles, method of regulating the color of the nanoparticles, and electrode and transmitted light-regulator each using the nanoparticles |
US20100215587A1 (en) | 2009-02-23 | 2010-08-26 | Kent State University | Materials and methods for mri contrast agents and drug delivery |
US20100254912A1 (en) | 2009-04-03 | 2010-10-07 | Kent State University | Gadolinium containing prussian blue nanoparticles as nontoxic MRI contrast agents having high relaxivity |
Non-Patent Citations (3)
Title |
---|
Lebel (2010) Advances in Magnetic Resonance Imaging of the Human Brain at 4.7 Tesla, Doctor of Philosophy Biomedical Engineering, p. 1-168. * |
Okubo et al. (J. Phys. Chem. Lett. 2010, 1, 2063-2071). * |
R Martinez-Garcia, et al., "Magnetic interaction between manganese (2+) atoms through aquo bridges and bifurcated cyano groups", Journal of Physics: Condensed Matter, Jan. 15, 2007, 1-11,IOP Publishing Ltd., UK; online at stacks.iop.org/JPhysCM/19/056202. |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3354375A1 (en) | 2017-01-27 | 2018-08-01 | Universite Paris Nord | Nanomaterial and method of production of a nanomaterial for medical applications, such as mri or sers |
WO2018138280A1 (en) | 2017-01-27 | 2018-08-02 | Universite Paris Nord | Nanomaterial and method of production of a nanomaterial for medical applications, such as mri or sers |
Also Published As
Publication number | Publication date |
---|---|
WO2012108856A1 (en) | 2012-08-16 |
US20130302256A1 (en) | 2013-11-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8092783B2 (en) | Gadolinium containing prussian blue nanoparticles as nontoxic MRI contrast agents having high relaxivity | |
US9198988B2 (en) | Nanoparticulate manganese MRI contrast agents | |
AU686523B2 (en) | Treated apatite particles for medical diagnostic images | |
Garcia et al. | Biological effects of MRI contrast agents: gadolinium retention, potential mechanisms and a role for phosphorus | |
EP1960002B1 (en) | Aqueous dispersions of superparamagnetic single domain particles production and use thereof for diagnosis and therapy | |
HUT74435A (en) | Contrast-materials containing melanin-derivatives | |
US5595724A (en) | Treated calcium/oxyanion-containing particles for medical diagnostic imaging | |
JPH05506227A (en) | Polymers as contrast agents for magnetic resonance imaging | |
US9808540B2 (en) | Contrast agent for nuclear magnetic resonance imaging comprising melanin nanoparticles stably dispersed in water | |
Smeraldo et al. | New strategies in the design of paramagnetic CAs | |
US20230087639A1 (en) | Biogenic hemin-based mri contrast agents, and compositions and methods thereof | |
EP1126785B1 (en) | Manganese compositions and methods for mri | |
Laranjeira et al. | Enhanced biosafety of silica coated gadolinium based nanoparticles | |
US8940275B2 (en) | Nanoparticles based on gadolinium coordination polymers as highly sensitive T1 MRI contrast agents | |
JP4361970B2 (en) | Method for T1-weighted nuclear magnetic resonance imaging of reticuloendothelial (RES) organs | |
US5716598A (en) | Contrast medium for magnetic resonance imaging using physiologically tolerable manganese compound | |
Shokouhimehr | Prussian blue nanoparticles and its analogues as new-generation T1-weighted MRI contrast agents for cellular imaging | |
US20230158177A1 (en) | Hypoxia-targeting contrast agent and methods of use thereof | |
Zhou et al. | Preparation and evaluation of a radioisotope-incorporated iron oxide core/Au shell nanoplatform for dual modality imaging | |
JPH0680588A (en) | Contrast medium for mri | |
Woodward et al. | 10 Magnetic Contrast Imaging | |
JP3729514B2 (en) | Contrast composition for MRI diagnosis | |
CN115518166A (en) | PH-responsive T1 enhanced MRI contrast agent and preparation method and application thereof | |
CN115721739A (en) | Contrast agent for pyelonephritis nuclear magnetic angiography and application thereof | |
CN109939245A (en) | A kind of paramagnetic nanoparticles material, preparation method and the purposes as mri contrast agent |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: KENT STATE UNIVERSITY, OHIO Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HUANG, SONGPING D;KHITRIN, ANATOLY K;PERERA, VINDYA S;AND OTHERS;REEL/FRAME:030795/0081 Effective date: 20110826 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2551); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY Year of fee payment: 4 |
|
FEPP | Fee payment procedure |
Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
LAPS | Lapse for failure to pay maintenance fees |
Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY |
|
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20231201 |